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Design, Synthesis and Evaluation of the Effect of Chalcones and Acyl-Hydrazones Derivatives on Alzheimer's disease biochemical targets. In silico study of the Pharmacokinetic Properties and in vitro toxicity.

Grant number: 18/02879-3
Support type:Regular Research Grants
Duration: November 01, 2018 - January 31, 2021
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Wanda Pereira Almeida
Grantee:Wanda Pereira Almeida
Home Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Assoc. researchers:Daniel Fábio Kawano ; euzebio guimarães barbosa ; Marcelo Lancellotti

Abstract

Alzheimer's Disease (AD) is multifactorial and requires the investigation of potential drug candidates to act on different neuropathological targets. Among these, the cholinergic deficit, the beta-amyloid peptide (A²), excitotoxicity, neuroinflammation and neurofibrillary tangles are the most relevant. A² peptide is formed by the abnormal processing of amyloid protein precursor (APP) by g and ²-secretase (BACE-1). It has been demonstrated that A² peptide, mainly that contains forty-two amino acid residues, plays a central role in AD, because it is related to the others pathological events, such as: formation of oligomers and fibrils, that injure the synapses in the brain; activation of microglia and astrocytes triggering a neuroinflammatory process; formation of neurotoxic complexes with acetylcholinesterase (AChE), through its peripheral anionic site (PAS); interaction with copper and zinc ions, leading to the oligomers stabilization, in addition to the generation of reactive oxygen species (ROS); A² promotes calcium dyshomeostase and excitotoxicity; it also alters kinases (GSK-3²) and phosphatases leading to the formation of intracellular neurofibrillary tangles. The above mentioned importance of A² encouraged us to study the effect of some acyl-hydrazone and chalcone derivatives on several biomarkers of AD. Based on promising results, we propose in this project the synthesis and evaluation of novel acyl-hydrazones and chalcones, against A² aggregation, AChE and BACE-1 activity. In silico studies of the pharmacokinetic profile and in vitro cytotoxicity will be also conducted. (AU)